Chu Zhiguo, Moenter Suzanne M
Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
J Neurosci. 2006 Nov 15;26(46):11961-73. doi: 10.1523/JNEUROSCI.3171-06.2006.
The brain controls fertility through release of gonadotropin-releasing hormone (GnRH), but the mechanisms underlying action potential patterning and GnRH release are not understood. We investigated whether GnRH neurons exhibit afterdepolarizing potentials (ADPs) and whether these are modified by reproductive state. Whole-cell current-clamp recordings of GnRH neurons in brain slices from ovariectomized mice revealed a slow ADP (sADP) after action potentials generated by brief current injection. Generating two or four spikes enhanced sADP amplitude and duration. sADP amplitude was not affected by blocking selected neurotransmitter/neuromodulator receptors, delayed-rectifier potassium channels, calcium-dependent cation channels, or hyperpolarization-activated cation channels but was halved by the calcium channel blocker cadmium and abolished by tetrodotoxin. Cadmium also reduced peak latency. Intrinsic mechanisms underlying the sADP were investigated using voltage-clamp protocols simulating action potential waveforms. A single action potential produced an inward current, which increased after double and quadruple stimulation. Cadmium did not affect current amplitude but reduced peak latency. Pretreatment with blockers of calcium-activated potassium currents (I(KCa)) reproduced this shift and blocked subsequent cadmium-induced changes, suggesting cadmium changes latency indirectly by blocking I(KCa). Tetrodotoxin abolished the inward current, suggesting that it is carried by sodium. In contrast, I(KCa) blockers increased the inward current, indicating that I(KCa) may oppose generation of the sADP. Strong sADPs were suprathreshold, generating repetitive spontaneous firing. I(ADP), sADP, and excitability were enhanced by in vivo estradiol, which triggers a preovulatory surge of GnRH release. Physiological feedback modification of this inward current and resulting sADP may modulate action potential firing and subsequent GnRH release.
大脑通过释放促性腺激素释放激素（GnRH）来控制生育能力，但动作电位模式和GnRH释放背后的机制尚不清楚。我们研究了GnRH神经元是否表现出后去极化电位（ADP），以及这些电位是否会因生殖状态而改变。对去卵巢小鼠脑片上的GnRH神经元进行全细胞电流钳记录发现，在短暂电流注入产生动作电位后会出现缓慢的ADP（sADP）。产生两个或四个尖峰可增强sADP的幅度和持续时间。sADP的幅度不受阻断选定的神经递质/神经调质受体、延迟整流钾通道、钙依赖性阳离子通道或超极化激活阳离子通道的影响，但钙通道阻滞剂镉可使其减半，河豚毒素可将其消除。镉还缩短了峰值潜伏期。使用模拟动作电位波形的电压钳方案研究了sADP的内在机制。单个动作电位产生内向电流，并在双重和四重刺激后增加。镉不影响电流幅度，但缩短了峰值潜伏期。用钙激活钾电流（I(KCa)）阻滞剂预处理可重现这种变化并阻断随后镉诱导的变化，这表明镉通过阻断I(KCa)间接改变潜伏期。河豚毒素消除了内向电流，表明它是由钠携带的。相反，I(KCa)阻滞剂增加了内向电流，表明I(KCa)可能对抗sADP的产生。强烈的sADP超过阈值，产生重复性自发放电。体内雌二醇可增强I(ADP)、sADP和兴奋性，雌二醇会引发GnRH释放的排卵前激增。这种内向电流和由此产生的sADP的生理反馈调节可能会调节动作电位发放和随后的GnRH释放。
